Indolocarbazoles. 1. Total synthesis and protein kinase inhibiting characteristics of compounds related to K-252c.

doi:10.1016/S0960-894X(00)80013-X

Bioorganic & Medicinal Chemistry Letters

Volume 3, Issue 8, August 1993, Pages 1537-1542

https://doi.org/10.1016/S0960-894X(00)80013-X Get rights and content

Abstract

The condensation of indolo[2,3-a]-carbazole (12) with 2,5-dimethoxytetrahydrofuran derivatives gave cyclofuranosylated compounds (e.g. 13), which were converted via dibromocompounds to the dinitriles (e.g. 25). Hydrolysis, hydrolysis-reduction and thiolysis afforded imides, lactams (e.g. 27) and their thio analogs. These compounds were potent inhibitors of the protein kinase C family.

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The indolocarbazoles, in particular indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives, are an important class of natural products that exhibit a wide range of biological activities. There has been a plethora of synthetic approaches to this family of natural products, leading to advances in chemical methodology, as well as affording access to molecular scaffolds central to protein kinase drug discovery programmes. In this review, we compile and summarise the synthetic approaches to the indolo[2,3-a]pyrrolo[3,4-c]carbazole derivatives, spanning the period from their isolation in 1980 up to 2020. The selected natural products include indolocarbazoles not functionalised at indolic nitrogen, pyranosylated indolocarbazoles, furanosylated indolocarbazoles and disaccharideindolocarbazoles.
An account of synthetic strategies towards indolocarbazole alkaloids: Arcyriaflavin A and staurosporinone
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In the following years these alkaloids were also reported from marine sources viz.; the marine acsidian Eudistoma sp. collected off the coast of West Africa [6] and from the actinomycete strain, Z2039-2, collected on the coast of Qingdao, China [7]. Like many other ICZ alkaloids, 6 and 7 also possess some interesting biological activities [8,9] and have thus been attractive targets for many synthetic and medicinal chemists. This review presents various synthetic strategies developed for the total synthesis of these two alkaloids till date.
An account of synthetic methods developed for indolocarbazole alkaloids arcyriaflavin A and staurosporinone is presented. Based on a common pathway or key intermediate involved, all these methods are broadly grouped into four categories: 1) using bisindolyl maleimide/anhydride, 2) from bisindoles, 3) using Fischer indolisation, 4) involving nitrene insertion. This review discusses in detail the strategies involved in the construction of these two molecules.
2,2′-Biindolyl Reactions with Aldehydes
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2,2′-Biindolyl has been condensed with aromatic and aliphatic aldehydes and products featuring 10-membered rings have been obtained. Thus, benzaldehyde gave compound 24a as the primary product, which readily underwent transannular oxidative coupling to 25a. The structures of both compounds were confirmed by X-ray crystallography. The product from 2,2′-biindolyl and formaldehyde under strongly acidic conditions was slightly different leading to compound 11, whose structure also was confirmed by X-ray crystallography. In this case, two molecules of 2,2′-biindolyl reacted with six molecules of formaldehyde.
Studies on cyclin-dependent kinase inhibitors: Indolo-[2,3-a]pyrrolo[3,4-c]carbazoles versus bis-indolylmaleimides
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A series of indolo[2,3-a]pyrrolo[3,4-c]carbazoles and their bis-indolylmaleimides precursors have been prepared in order to compare their activity as D1–CDK4 inhibitors. Both enzymatic and antiproliferative assays have shown that the structurally more constrained indolo[2,3-a]pyrrolo[3,4-c]carbazoles are consistently more active (8–42-fold) in head-to-head comparison with their bis-indolylmaleimides counterparts. Cell-cycle analysis using flow cytometry have also shown that the indolocarbazoles are selective G1 blockers while the bis-indolylmaleimides arrest cells in the G2/M phase.
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¹: Department of chemical research.

²: Departments of pharmacology and tumor biology.

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Indolocarbazoles. 1. Total synthesis and protein kinase inhibiting characteristics of compounds related to K-252c.

Abstract

Trends Pharmacol. Sci.

J. Natl. Cancer Inst.

Bull. Chem. Soc. Jpn.

Tetrahedron Lett.

Helv. Chim. Acta

Annalen

Nature

Science

Br. J. Cancer

Trends Pharmacol. Sci.

Drug Res.

Drugs Exptl. Clin. Res.

Biochem. Pharmacol.

Cancer Res.

J. Antibiotics

J. Med. Chem.